Abstract
Interindividual heterogeneity in the disease progression of HIV-1-infected patients receiving long-term antiretroviral therapy suggests that some host-related factors may have limited treatment efficacy. To understand the nature of factors contributing to treatment failure, we performed a retrospective cohort study of 45 chronically HIV-1-infected individuals sharing a similar demographics and route of infection, compared the differences between virologically suppressed (VS) and treatment failure (TF) patients with respect to clinical, immunological and virological characteristics. We found that the baseline diversity of HIV-1 env quasispecies was the major difference between VS and TF group, and higher baseline diversity in TF patients. We further predicted TF-related env mutations using a selection pressure-based approach, followed by an analysis of these mutations based on the available three-dimensional structures of gp120/gp41 or their complexes with neutralizing antibodies. Notably, almost all of the identified residues could be mapped to the epitopes of known HIV-1 neutralizing antibodies, especially the epitopes of broadly neutralizing antibodies, and these mutations tended to compromise antibody-antigen interactions. These results indicate that the escape of HIV-1 from host humoral immunity may play a direct role in TF in long-term antiretroviral-experienced patients and that based on env gene sequence of the viruses in the patients.
Highlights
Rapid replication dynamics and high mutation rate of human immunodeficiency virus type 1 (HIV-1) allows the virus to evolve continuously and quickly during the course of infection[1]
These results demonstrate that the escape of HIV-1 from host humoral immunity contributes to disease progression in patients on long-term antiretroviral therapy (ART)
Humoral responses evolve in response to these envelope glycoprotein (Env) escape mutations, but the kinetics of evolution does not correlate with the rate of disease progression[6]
Summary
Rapid replication dynamics and high mutation rate of human immunodeficiency virus type 1 (HIV-1) allows the virus to evolve continuously and quickly during the course of infection[1]. Considerable variation of the virus is observed among patients in response to treatment, with a substantial proportion of individuals experiencing treatment failure, including virologic failure, i.e., inability to achieve or maintain suppression of viral replication; immunologic failure, i.e., failure of CD4 count to increase; and subsequent clinical failure[4, 5] This interindividual heterogeneity in disease progression suggests that some host-related factors may have affected the effectiveness of ART. The escape mutants in the envelope glycoprotein (Env) during early HIV-1 infection primarily involved changes in N-linked glycosylation that could sterically inhibit the accessibility of neutralizing epitopes[11, 15] All these findings suggest a critical role of selective pressure exerted by host humoral immune response in driving HIV-1 evolution. These results demonstrate that the escape of HIV-1 from host humoral immunity contributes to disease progression in patients on long-term ART
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